#268 – The truths about obesity, skinny fat, TOFI & why thin people can be unhealthy | Dr. Robert Lustig & Mike Haney

The obesity epidemic isn’t about calories-in-calories-out. Instead, chronic stress and high insulin levels from refined carbs and sugar are drivers of fat storage. And the type of fat stored matters, since visceral fat accumulation leads to worsening metabolic health. Dr. Robert Lustig and Mike Haney discuss the different types of fat and how they are stored and burned; what thin on the outside, fat on the inside means; whether people can be healthy at any size; environmental factors that contribute to obesity; and what people can do to manage weight.

09:40 — Three things are required for fat storage to occur

Weight management isn’t about calories-in-calories out.

So you need an adipocyte, and you need insulin, and you need excess energy. You have those three things, and you’re going to get more body fat. If you eat more than you burn, you will generate some extra body fat. But there are other ways to generate that excess body fat aside from caloric excess. And that is sort of the key to obesity. Because there are people who gain weight even when they’re not eating very much. And people say, “That’s not possible. The first law of thermodynamics says it has to be energy excess.” No, actually it doesn’t. There are ways to change that calculus. For instance, what if your mitochondria which are doing the burning, are not as efficient? What if they are not turning that energy into ATP at the same rate? Let’s say they’re 1% less effective at burning energy as control. Okay, that 1% is going to generate a whole lot of body fat in a very short period of time with no change in food intake.  So, you know, this is a relatively complex dynamic and there are a lot of factors at play.

21:54 — The key to fat loss is reducing insulin

Insulin drives fat storage. Preventing insulin spikes aids with weight management.

The goal is: get the insulin down. And I can’t stress this enough. When I was running the obesity clinic at UCSF, which I did for 17 years, about four years into it, I started putting all of this together in terms of how body metabolism worked. And I ended up doing some seminal research demonstrating that it was the insulin that determined the weight gain and that getting the insulin down was essential for weight loss, which turns out to be completely true and has stood up to the test of time. And I’m very proud of that work. Point is, I turned my obesity clinic into an insulin-reduction clinic. Get the insulin down any way you can. What’s the easiest way to get insulin down? Don’t let it go up. Well, what makes it go up? Refined carbohydrate and sugar.

23:39 — Refined carbohydrates lead to fat storage

You can prevent high insulin by eliminating refined carbohydrates and sugar from your diet. When eating carbohydrates, focus on those that are fiber rich.

Now, I am not a ketogenic diet proponent, okay? And I’ve said this many times. There are many ways to skin this cat, okay? There are a whole bunch of people who can lose weight on a high-carbohydrate, low-fat diet. But if they’re going to do that, then it can’t be refined carbohydrate. And it can’t be sugar. Well, if it’s not refined carbohydrate, that means it’s carbohydrate with fiber, because that’s the difference between refined and unrefined. Well, it turns out the fiber is extraordinarily important in this story because it’s going to reduce the rate of absorption in the intestine of glucose being brought into the bloodstream. Therefore, that’s going to reduce the size of the glucose spike. Something Levels is of course very interested in doing—that’s why we do what we do. And that will reduce the blood level of glucose. Therefore that will reduce the insulin response of the pancreas, because the pancreas only knows what the blood glucose is. So, if you can keep that blood glucose down, you can keep the blood insulin down. And if you can keep the blood insulin down, then your fat cells have a chance at being able to give up their fat.

32:41 — What is metabolically healthy obesity?

The body can accumulate around 25 pounds of subcutaneous fat before metabolic health status changes.

So, the damage that the cell death from subcutaneous adipose tissue causes from a metabolic standpoint is relatively small. So how many kilos or how many pounds of subcutaneous fat can you gain before you start reaching thresholds of cytokines in your bloodstream that then go to the liver and cause damage? And the answer is, About 22 to 25 pounds, about 10 kilos. So you can basically gain 10 kilos of subcutaneous fat and not notice it metabolically. Now, you may notice it mechanically. You may notice it in terms of your performance going down. You may notice it in terms of your knees hurting when you go upstairs. You may notice it  in multiple other ways from a mechanical standpoint. That’s possible. But your body won’t notice it from a metabolic standpoint, because the cytokine concentration from those dead adipocytes in that subcutaneous fat will not have reached a level that is going to cause difficulty at the level of the liver or the difficulty at the level of any other cell in terms of how they’re functioning. We call this “metabolically healthy obesity” because you haven’t reached that level that altered the metabolic status of the rest of the body, even though cells in the subcutaneous space are starting to die.

42:05 — Visceral fat causes “metabolic mayhem”

Visceral fat alters metabolic health by sending cytokines to the liver, causing damage.

Visceral fat will cause more metabolic perturbation and more damage from those cytokines reaching the liver because it was visceral adipose tissue versus subcutaneous adipose tissue, even though the adipocytes themselves are not all that different. The visceral adipose tissue makes more metabolic mayhem.

45:40 — What is thin on the outside fat on the inside?

TOFI stands for thin on the outside, fat on the inside. The acronym refers to people who appear thin but have excess visceral fat.

How many pounds or kilos of fat can your liver store before it gets sick? Half a pound. Half a pound of fat before your liver starts manifesting metabolic dysfunction. So 22 to 25 pounds of subcutaneous fat equals 3 to 5 pounds of visceral fat equals a half a pound of liver fat in terms of metabolic mayhem. And can you measure half a pound on the scale? No way in hell. So there are people who have liver fat who are perfectly normal weight who think they’re fine, and they’re not. And this is what we call thin on the outside, fat on the inside, TOFI. So it’s the ectopic fat, the visceral fat, the liver fat that ultimately determines the degree of metabolic dysfunction.

50:27 — Stress causes the accumulation of visceral fat

Cortisol levels go up from stress, especially chronic stress, which drives the storage of visceral fat that can be used as energy to respond to threats. However, in today’s world, where sedentary lifestyles are prevalent, we’re less likely to recruit that visceral fat for energy.

So what is so dysfunctional about stress? Two things. One, the cortisol, which we just mentioned, cortisol, is a driver of adipose tissue deposition. And the reason is because if you’re stressed, your body is saying, “Oh, I better put some energy in a place I can access it quickly because I might need it to run away from the lion” . . . We don’t have chronic stress due to avoiding the lion on the Savannah; we have chronic stress due to our sedentary lifestyle.

58:06 — Exercise helps burn visceral fat

Exercise, when done consistently, can be a helpful tool for reducing visceral fat.

So you will get that visceral fat to give up its lipid first. And that’s one of the reasons why doctors will tell you, “Well, if you just lost like 3% of your body weight, you’d get healthy.” That’s right. And the reason is because that 3% would be your visceral fat. It’s not going to be subcutaneous fat, promise. It ain’t going to change how you look in a bathing suit, but it is going to make you metabolically healthier. And the reason is because your visceral fat will get burned off by that exercise first.

01:00:58 — The key to being healthy

Mike Haney and Dr. Rob Lustig sum up the main points to focus on for weight management and metabolic health.

So diet, what you eat, is going to play a role. How much you eat and what you eat is going to play a role in just that baseline question of how much extra adipose tissue am I packing on? That’s correct. And exercise and stress are going to play a role in where that fat accumulates, and where that fat gets burned off. So you essentially need that triad to work together. You need to be eating in such a way that you’re not directing that fat to the liver. So, less sugar, less alcohol. You need to eat in such a way that you’re not driving the insulin up. Because that’s going to drive more fat storage and then you need to exercise to help burn off that visceral fat.  The key to being healthy. That’s it. Good, we’ve solved it. Diet and exercise. But not eat less, exercise more. Okay, it’s very specific and it has very specific targets within the body in order to make it work.

1:06:12 — Endocrine-disrupting chemicals also play a role in obesity

Some endocrine-disrupting chemicals are considered “obesogens” that drive fat storage, independent of calories.

In addition, we have a whole host of chemicals that are in our environment. We call them environmental obesogens. An obesogen is a chemical that induces adiposity, separate from its caloric content. Most of these environmental obesogens don’t have calories. Like BPA doesn’t have calories. Phthalates don’t have calories. Parabens don’t have calories. PFAS don’t have calories. But they are strewn throughout our entire environment, and they inhibit mitochondria. They inhibit mitochondria in the same way fructose does. And so you’re going to end up taking the substrate and turning it into fat.

1:26:46 — Is there such a thing as “health at any size”?

Yes, but Dr. Rob Lustig clarifies that subcutaneous fat isn’t the issue; visceral and liver fat are the health concerns with obesity.

What I would rather call it is subcutaneous fat at any size. I don’t care what your subcutaneous fat is, okay? So, if you are obese and it’s because of subcutaneous fat, fine, no problem. You do you. It’s a non-issue. It’s a non-issue medically, and it should be a non-issue culturally. Subcutaneous fat is personal and not the problem. Visceral and liver fat is the problem. Now, as it turns out, visceral and liver fat occurs in normal weight people as well as obese people. The “healthy at any size” is missing the point about the three components. If you have visceral and liver fat, it is in your best interest and ultimately society’s best interest from a medical care standpoint to do something about it.

Rob Lustig (00:00:07):

Self-control is basically just personal responsibility turned inward. There is no personal responsibility, and we know that because obesity is a biochemical problem, not a behavioral one. People think if you eat it, you better burn it or you’re going to store it. Wrong. Wrong. It’s more if you’re going to store it and you expect to burn it, then you’re going to have to eat it, in which case the two behaviors we associate with obesity, the gluttony and the sloth are actually secondary to the biochemical process of the insulin going up. So it’s the insulin that’s driving the behaviors, and we’ve proven that. Things that make your insulin go up, generate those behaviors irrespective. And unfortunately, a lot of the things that make insulin go up are things in the environment that have nothing to do with your behaviors.

Ben Grynol (00:01:05):

I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health, and along the way, we have conversations with thought leaders about research-backed information so you can take your health into your own hands. This is a whole new level. Obesity, it’s an ongoing conversation and a hot-button topic that never loses steam in the social fabric that we navigate about health and wellness. And so Haney, Mike Haney, our editorial director, he was curious to answer the question, how unhealthy is obesity itself. And no one better to tap than our good friend and Levels advisor Dr. Rob Lustig. He’s a New York Times bestselling author, and he’s no stranger to the show. He’s written a number of books on obesity and he studied it widely in his practice. Obesity Before Birth and Fat Chance, those are two of the books that he’s written on the topic.

(00:02:12):

And so Haney sat down with Rob and they discussed this idea of some of the downsides of obesity. There’s the orthopedic, that’s the physical or the mechanical components of being obese, things like there being more pressure on your joints and it being harder on your body when you are obese. And there’s the metabolic component, which really depends where the obesity is. If you’ve got visceral fat, that’s fat around your organs, that is more of an issue than subcutaneous fat. And so fat, it builds from not just being in a caloric surplus, but it really depends on how effectively mitochondria are functioning.

(00:02:46):

If you’ve got mitochondrial dysfunction and the cells are not processing energy effectively, then it can lead to fat buildup over time. Haney was also curious about this idea of how much does the amount of dietary fat that someone consumes impact whether or not they become obese. And Rob’s take is that it’s not really about the amount of dietary fat that anyone eats, it’s more about the amount of insulin that’s generated while you’re eating fat. Because really insulin determines weight gain, and getting insulin down is essential for weight loss.

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Lastly, Haney and Rob talked about this idea of childhood obesity and how it can really start in utero based on the diet that the mother consumes, as well as some of the impact from other biomarkers such as cortisol that can increase depending on a situation that a mother is in at any given time or other environmental factors. The main takeaway is that people should focus on being metabolically fit as opposed to just focusing on losing weight. The key is eliminating visceral fat, improving mitochondrial function, and getting insulin down. If people can do that, that is the foundation for positive metabolic health. Anyway, no need to wait. Here’s Haney and Rob.

Mike Haney (00:04:03):

So the topic today is obesity, and I’ll just lay the cards on the table. The question I really want to answer, that every time we write something about obesity or I read something about obesity is: How unhealthy is obesity in and of itself? And just to level set where I’m coming from with that argument. I think on one side of this question, you’ve got historically the… We know now from a lot of research, there’s a lot of discrimination, a lot of bias against obesity. It’s led to a lot of misdiagnosis, to a lot of just poor medical outcomes from just not treating it appropriately, not thinking about it, not to mention whatever psychological damage from people being shamed, etc.

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As a probably reaction to that on the other side, you’ve got the healthy at any size, obesity is not a problem, hey, we’re all built different, and lots of spectrum within that side of the debate as well. And so we’re always just trying to get people healthy. That’s the goal. I don’t really care what you look like, I don’t really care what you do, we just want folks to be as healthy as they can be. That’s what’s really informing this discussion is us trying to figure out how do we talk about obesity, how do we hone in on the physiological component of it, and what we know and don’t know crucially about that physiological effect on overall health status. So maybe let’s just start with what’s actually going on physiologically in your body when we talk about obesity. What is fat doing in your body?

Rob Lustig (00:05:41):

Before we approach that question, first I want to address the question you started with, which is: What are the downsides of obesity and is it particularly problematic? There are two buckets that we can talk about with respect to obesity. One is the mechanical downsides. For instance, the orthopedic like knee problems and walking problems, ambulatory problems. And then there’s the metabolic, the associated diseases, the cardiovascular disease, the diabetes, the cancer, the dementia. So mechanical metabolic. The mechanical will be true no matter what kind of obesity. The metabolic depends on where the obesity is. So we need to be able to separate those two. And as we discuss them, we’ll put them into one of the two bins.

(00:06:47):

All right. So the question you asked is how bad for you is obesity? And the answer is, it depends. What is energy doing inside your body? Well, the goal is for energy to be burned. And when it’s burned, you create a chemical in your cells called ATP, adenosine triphosphate. That is the chemical energy that every cell in your body needs in order to be able to perform the functions it needs to do to stay alive. So to run all the molecular motors, to basically transform one chemical into another, to be able to grow and divide, all of these things are dependent on having a source of energy that the cell can use, and that is stored in this thing called ATP. So that’s what your body wants to do with energy. Now, when excess energy comes into the body, it doesn’t want to just lose it, it doesn’t just want to turn it into heat, it wants to store it because it doesn’t know when the next meal is coming. You may know, but it doesn’t know.

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And so there is a relatively inefficient process of turning that extra or excess energy that comes in by food into the most efficient but not all that good for you storage form, which is lipid, which is body fat. And lipid is much more energy-dense than glycogen, which is the other storage form of energy. Lipid is nine calories per gram if you blew it up in a bomb calorimeter, and glycogen would be four calories per gram. And so lipid is more energy dense, therefore you can pack more energy into a smaller volume. Therefore, lipid is the preferred source of energy storage. Now, in order to turn that energy into lipid, you need an adipocyte and you need insulin. And the reason you need those is because adipocyte is the preferred energy storage form factor, if you will. That’s where your body wants to put the excess energy. And you need insulin because insulin is the gateway, the key to the door that allows the excess energy to get into the adipocyte in the first place.

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So you need an adipocyte and you need insulin and you need excess energy. You have those three things and you’re going to get more body fat. Now, if you eat more than you burn, you’ll generate some extra body fat. But there are other ways to generate that excess body fat aside from caloric excess, and that is the key to obesity. Because there are people who gain weight even when they’re not eating very much. And people say, “That’s not possible. The first law of thermodynamics says it has to be energy excess.” No, actually it doesn’t. There are ways to change that calculus. For instance, what if your mitochondria which are doing the burning are not as efficient? What if they are not turning that energy into ATP at the same rate? Let’s say they’re 1% less effective at burning energy as control. That 1% is going to generate a whole lot of body fat in a very short period of time with no change in food intake.

(00:10:58):

This is a relatively complex dynamic and there are a lot of factors at play. So there’s the food. There’s also the rest of the environment because there are things in the environment that trigger that process. We call them environmental obesogens. We have the mitochondria and whether or not they are keeping up or not. And of course, we have things like energy expenditure, bodily activity, even the heat versus the cold and the environment, and your altitude, how high you live. Because if you live at a high elevation then you have to have more mitochondria because you have less oxygen. So there are a whole bunch of things that go into this soup that determines whether or not any molecule of energy, whether it be glucose or fat, will end up turning into body weight in terms of adipocyte storage. This is a complex problem.

Casey Means (00:12:11):

This is Dr. Casey Means, co-founder of Levels. If you’ve heard me talk on other podcasts before, you know that I believe that tracking your glucose and optimizing your metabolic health is really the ultimate life hack. We know that cravings, mood instability, and energy levels, and weight are all tied to our blood sugar levels. And of course, all the downstream chronic diseases that are related to blood sugar are things that we can really greatly improve our chances of avoiding if we keep our blood sugar in a healthy and stable level throughout our lifetime. So I’ve been using CGM now on and off for the past four years since we started Levels, and I have learned so much about my diet and my health. I’ve learned the simple swaps that keep my blood sugar stable like flax crackers instead of wheat- based crackers. I’ve learned which fruits work best for my blood sugar. I do really well with pears and apples and oranges and berries, but grapes seem to spike my blood sugar off the chart.

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I’m also a notorious night owl, and I’ve really learned with using Levels. If I get to bed at a reasonable hour and get good quality sleep, my blood sugar levels are so much better. And that has been so motivating for me on my health journey. It’s also been helpful for me in terms of keeping my weight at a stable level much more effortlessly than it has been in the past. So you can sign up for Levels at levels.link/podcast. Now, let’s get back to this episode.

Mike Haney (00:13:47):

One question I want to ask just to follow up on that notion of mitochondria and the idea that if they’re 1% less efficient, that’s going to lead to more fat. So is it the case that if the mitochondria are less efficient at burning the fat-

Rob Lustig (00:14:01):

Well, less efficient at burning the glucose.

Mike Haney (00:14:04):

Okay, less efficient at burning… Well, I would’ve interpreted that to mean I’m simply getting less energy out of the burning of the same amount of energy. Whether that’s glucose or fat or whatever, I’m just going to get less current out of that process. But is it that we’re actually burning less of the stored energy that we have, therefore there’s just more stored energy stays on me?

Rob Lustig (00:14:33):

Basically what happens is the cell directs the energy to the mitochondria, and it does so in the form of a chemical called pyruvate. The pyruvate enters the mitochondria, it gets turned into another chemical called acetyl CoA. And then the acetyl CoA enters this thing we call the tricarboxylic acid or the Krebs cycle. And the Krebs cycle is the thing that actually generates the ATP. So for one glucose molecule, you’ll generate two ATP in the process called glycolysis, preparing the glucose for burning by the mitochondria to get to pyruvate. You get two out of that. And then the mitochondria will burn the pyruvate all the way to carbon dioxide and water, and you will get 36 ATP out of that. So the Krebs cycle, the tricarboxylic acid cycle is much more energy intensive and much more energy efficient in terms of generating that ATP. Those mitochondria have to be able to keep up.

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Now, there are things that happen to mitochondria that makes them less adept at being able to do that, how fresh your mitochondria are versus how old your mitochondria are, whether the enzymes in the mitochondria are actually doing their job at peak capacity. And there are some things that can actually diminish that. So environmental obesogens often work at the mitochondria to diminish their capability of being energy efficient. If they don’t push as much energy through those mitochondria because they’re energy inefficient, then you’re going to get an excess buildup of intermediate, and then that excess intermediate will get shuttled out as fat. It will get turned into fat in the cell through a process called de novo lipogenesis, new fat-making. Taking carbohydrate, taking substrate from carbohydrate pyruvate and turning it into fatty acetyl CoA, which then becomes triglyceride.

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And then the liver has to do something with it. It will either shuttle it out in the form of VLDL to be taken up by the adipocyte with the influence of insulin, or it will stay in the liver and never make it out, and now you’ve got fatty liver disease. So you can end up with obesity and high triglycerides, or you can end up with fatty liver. Either way, you’ve got different problems related to obesity. But they’re not necessarily the same problems because it may be mechanical because of the adipocyte, excess weight, or it may be metabolic because of the problem in the liver. So it depends on where the problem is as to what the manifestations of the problem will be.

Mike Haney (00:17:44):

So let’s stay on this topic of energy burning and the role of fat tissue or adipocytes within your body. We often say that your body can burn two… Or high level is, your body can burn two fuel sources, glucose or fat. If it’s burning fat, you’re actually making ketones, and that’s what your body is burning. But glucose can also become fat. Explain these two fuel sources. And when we say your body is burning these things, what’s actually happening? Are we really switching between two fuel sources like diesel and unleaded, or is everything becoming the same thing which then gets burned?

Rob Lustig (00:18:21):

Ultimately, everything becomes the same thing. At the level of the mitochondria, they all become the same thing. When you say you’re burning fat, you don’t have to turn the fat into ketones to burn them. You can burn the fat directly. So the fat can come into the mitochondria and can be acted on by a bunch of enzymes that will cleave two carbon fragments out of it, never generating ketones. Ketones are the way you turn adipocyte fat into energy for the rest of the body. So if you eat dietary fat, that won’t become ketones. If you lose fat from peripheral sources like around your middle in order to be burned elsewhere, that will turn into ketones. But it doesn’t really matter because it will go into the mitochondria.

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And the great thing about burning fat or burning ketones either/or is you don’t need insulin to do it. Remember we talked about glucose, insulin, and the adipocyte before? Yeah, for glucose. But in fact, if it’s dietary fat and/or ketones will enter the cell without insulin. So if you’re insulin-resistant, you’re going to have a problem transporting that glucose. Whereas if you’re insulin-resistant, you won’t have any problem transporting that fat or those ketones. So that’s actually quite important in terms of metabolic adaptation and whether or not you should be consuming fat when you’re insulin-resistant or not.

Mike Haney (00:20:06):

So one last thing on that, and then we’re going to get back to the tissue level. You mentioned dietary fat in there. How much does the amount of dietary fat that I eat impact whether or not I become obese?

Rob Lustig (00:20:18):

So it’s not about the amount of dietary fat you eat, it’s the amount of insulin you generate while you’re eating that dietary fat. And the dietary fat’s not generating the insulin, the carbohydrate that comes along with the dietary fat is what’s generating the insulin. And it turns out though, that the more dietary fat while you’re generating the insulin, the higher the insulin spike. And this was work done many years ago by Dobbins and Southwestern in Dallas.

(00:20:51):

Your glucose tolerance test will change in terms of your insulin response based on how much dietary fat you consumed the day before. So if you ate a whole lot of dietary fat one day and then ate some carbohydrate the next day, that turns out to generate a bigger insulin response than if you hadn’t done that. Because basically, the pancreas is holding back because you ate all that dietary fat and it didn’t want to release it, and it’s now going to dump all that extra insulin the next time around. So basically, you have to train your pancreas. And that’s one of the things that the ketogenic diet does, is it basically trains your pancreas to release less insulin.

Mike Haney (00:21:39):

Okay, that’s where I wanted to go with that was to the keto diet and ketosis because that is a very low-carb, very high-fat diet, with the idea being that you’re going to force your body to burn fat rather than glucose.

Rob Lustig (00:21:54):

Because your insulin is low. The goal is get the insulin down. And I can’t stress this enough. When I was running the obesity clinic at UCSF, which I did for 17 years. About four years into it, I started putting all of this together in terms of how body metabolism worked. And I ended up doing some seminal research demonstrating that it was the insulin that determined the weight gain and that getting the insulin down was essential for weight loss, which turns out to be completely true and has stood up to the test of time. And I’m very proud of that work.

(00:22:37):

Point is, I turned my obesity clinic into an insulin reduction clinic. Get the insulin down any way you can. What’s the easiest way to get insulin down? Don’t let it go up. Well, what makes it go up? Refined carbohydrate and sugar. So getting rid of those two things brought the insulin way down. Therefore, there’s less insulin pressing on the adipocyte, which means that the adipocyte can give up the fat that’s stored in the form of ketones. That’s what the ketogenic diet does. And you can’t maintain ketosis unless you keep the insulin down. And so that’s why you can lose weight because there’s less insulin pressing on your adipocyte. That’s the only way to lose weight, in fact.

Mike Haney (00:23:35):

So talk about then weight loss if you don’t want to go on the keto diet.

Rob Lustig (00:23:39):

Well, then it’s harder. And the reason is because the insulin is going to respond to the carbohydrate in your diet because you didn’t go on the ketogenic diet. Now, I am not a ketogenic diet proponent, and I’ve said this many times. There are many ways to skin this cat. There are a whole bunch of people who can lose weight on a high-carbohydrate, low-fat diet.

PART 1 OF 4 ENDS [00:24:04]

Rob Lustig (00:24:02):

A high carbohydrate, low fat diet. But if they’re going to do that, then it can’t be refined carbohydrate and it can’t be sugar. Well, if it’s not refined carbohydrate, that means it’s carbohydrate with fiber because that’s the difference between refined and unrefined. Well, it turns out the fiber is extraordinarily important in this story because it’s going to reduce the rate of absorption in the intestine of glucose being brought into the bloodstream. Therefore, that’s going to reduce the size of the glucose spike something levels is of course very interested in doing. That’s why we do what we do, and that will reduce the blood level of glucose. Therefore, that will reduce the insulin response of the pancreas because the pancreas only knows what the blood glucose is.

(00:24:56):

So if you can keep that blood glucose down, you can keep the blood insulin down, and if you can keep the blood insulin down, then your fat cells have a chance at being able to give up their fat in order to turn them into ketones in order to be able to power the cells and lose weight at the same time. So it’s not that you can’t do it on a high-carbohydrate diet, but you have to be careful about the kind of carbohydrates you eat. And most people who are doing a high-carbohydrate diet are not particularly shall we say in the know on this.

Mike Haney (00:25:35):

So let’s get back to maybe beyond the mitochondria, the tissue level of fat and obesity. So I wrote down four words that come up all the time when we talk about this and we talk about fat, ectopic, subcutaneous, visceral, and adipose. What’s the difference between those four words?

Rob Lustig (00:25:52):

Well, adipose just means fat tissue.

Mike Haney (00:25:55):

Okay, so any fat tissue is adipose tissue?

Rob Lustig (00:25:58):

Any fat tissue is adipose tissue. Okay, so take that word off. Okay. Adipocytes, make up adipose tissue. Adipocytes are specialized cells that like to store energy as lipid. That’s what adipocytes are. So when we talk about the adipose, we’re talking about all the adipocytes. Now, some of those adipocytes are around your butt, big butt fat, subcutaneous fat. That’s where subcutaneous comes in. And some of those adipocytes are around your organs. We call that visceral fat. And then finally, there are cells in the liver that don’t want to store fat that end up storing fat. They’re not adipocytes. They’re not adipose tissue. But because the fat ends up there, you end up with fatty liver. And we have to talk about liver fat. So we have to talk about subcutaneous fat. We have to talk about visceral fat, and we have to talk about liver fat, those three.

Mike Haney (00:27:03):

So where does ectopic fit into that?

Rob Lustig (00:27:05):

So ectopic is visceral and liver. Ectopic means visceral and liver. So your body has the capability of putting some energy into visceral fat. The problem is visceral fat’s, very metabolically active fat. Subcutaneous fat is very metabolically inactive fat.

(00:27:29):

Subcutaneous fat is your spare tire. Subcutaneous fat is there for emergencies. It keeps layering on and layering on, and you get bigger and bigger. But from the standpoint of does it make the car too heavy to drive? No. Until you can’t layer on anymore. So subcutaneous fat is where your body wants to put the excess energy. Insulin drives the energy, the excess energy, the glucose or the lipid into the fat cells of the subcutaneous space, your big butt, if you will. Okay? Now is big butt fat, is subcutaneous fat bad for you? And the answer is no. Up to a point. Up to a point. So this gets a little complicated, but I’m going to do my best. Your total body fat cell number is determined by the time you’re age two, by age two. And the reason we know that is from some carbon-14 experiments from World War II and looking at the decay, Kristi Spalding from Karolinska demonstrated this back in the early 2000s. Wonderful research, really interesting.

(00:28:58):

But basically, your fat cell number for your entire body is determined by age two. After that, any increase in adipose tissue is adipose tissue growth, not adipose tissue number.

Mike Haney (00:29:14):

So cells getting bigger, not getting more cells?

Rob Lustig (00:29:16):

Exactly. The cell is getting bigger. So inside the adipocyte, inside that fat cell, there is a fat vacuole, a specialized storage place, the depot where the fat goes. So you’ve got your nucleus, you’ve got your mitochondria, not too many because it’s white adipose tissue, so not too many mitochondria. And you’ve got all the other things that fat cell needs, Golgi apparatus and lysosomes and all these other things that make up a cell. And you have this thing called a fat vacuole. And the fat vacuole has a border, and that border keeps the fat away from everything else. So it is basic… It’s not strewn all the way throughout the cell it is in this fat vacuole. Now the fat vacuole dump energy into it has as more lipid. And so the fat vacuole grows, and the fat vacuole grows and the fat vacuole grows. It gets bigger and bigger. At a certain point, that fat vacuole, which has this border around it, and the border is made up of a protein called perilipin, that perilipin border stretches so wide that it can’t maintain its integrity anymore. And when that happens, then the lipid actually spills into the rest of the cell. When that happens, it chokes off and kills it. Now you have a dead adipocyte with a lot of grease.

(00:30:59):

When that happens, the cytokines that are released, the proteins from the cell that basically signal injury circulate, go into the bloodstream and activate macrophages, the clean-up crew, the mop-up crew, the janitors to come clear out the grease. And so the macrophages invade the lipid, the adipose tissue I should say, and start cleaning it up. And the process, they generate more cytokines to get more janitors into the space. And so the cytokine level in your bloodstream, like TNF-alpha or IL-6, tumor necrosis factor alpha interleukin-6 will go up. Now when that happens, you can measure it in the bloodstream, but because it was in subcutaneous fat, the subcutaneous fat again is specialized fat that sits around your butt. It drains into the systemic circulation. Now, the systemic circulation is six liters. Okay? You have six liters of blood. So those cytokines will end up in the systemic circulation. And so unless you kill off a whole bunch of fat cells, it’s going to be really hard for those cytokines to generate any sort of meaningful concentration in a six-liter volume.

(00:32:41):

So the damage that the cell death from subcutaneous adipose tissue causes from a metabolic standpoint is relatively small. So how many kilos or how many pounds of subcutaneous fat can you gain before you start reaching thresholds of cytokines in your bloodstream that then go to the liver and cause damage? And the answer is about 22 to 25 pounds, about 10 kilos. So you can basically gain 10 kilos of subcutaneous fat and not notice it metabolically. Now, you may notice it mechanically, you may notice it in terms of your performance going down. You may notice it in terms of your knees hurting when you go upstairs. You may notice it in multiple other ways from a mechanical standpoint, that’s possible, but your body won’t notice it from a metabolic standpoint because the cytokine concentration from those dead adipocytes in that subcutaneous fat will not have reached a level that is going to cause difficulty at the level of the liver or at the difficulty at the level of any other cell in terms of how they’re functioning. We call this metabolically healthy obesity because you haven’t altered the metabolic status of the rest of the body, even though cells in the subcutaneous space are starting to die.

(00:34:29):

Now, metabolically healthy obesity, how common is that? Turns out that’s about 10%. Maybe 15% of the general obese population have metabolically healthy obesity. And the reason is because their dead adipocytes are all in the subcutaneous space and they haven’t generated enough of a cytokine level to be damaging to the liver or to the rest of the body.

Mike Haney (00:35:00):

Why is the number so low? If I’m following the sort of mechanics here, it sounds like essentially a volume game that as long as I’m only gaining 10, 15 pounds, that I’m probably good. And if I looked around the population of Americans, I would say there’s a lot of folks who are like 10, 15 pounds overweight, more of those folks than there are probably folks who are 100 pounds overweight. So I would think that that crowd of people in that lower level of overweight, which if I’m following, should be at least metabolically healthy, would be more than 10%.

Rob Lustig (00:35:34):

You’re assuming that everyone has the same fat cell number. They don’t. They start out at different places. For instance, African-Americans, for reasons that are still completely unknown, start out with a higher fat cell number. Therefore, it’s actually more likely that an African-American, even though they have a much higher incidence of obesity, will actually have metabolically healthy obesity because they had a higher fat cell number. Therefore, their perilipin border didn’t get as stretched for the same amount of weight, for the same amount of fat deposition because they have more places to put it.

(00:36:16):

Conversely, Asians, especially South Asians, for whatever reason, and we still don’t know the answer, why they start out with very few fat cells. And so when they gain a few extra pounds, they don’t have the place to put it. And so their perilipin border will stretch much greater as they’re laying down that fat. And so they will end up being sicker sooner at a lower body mass index, at a lower percent adiposity because they have fewer fat cells to start with. It depends on what the size of your bucket is before you start accumulating.

Mike Haney (00:37:01):

So that 20 to 25 pound number of that sort of threshold-

Rob Lustig (00:37:05):

That’s for Caucasians.

Mike Haney (00:37:07):

And that will vary then depending on that fat cell number-

Rob Lustig (00:37:12):

That you start with.

Mike Haney (00:37:13):

… That you start with.

Rob Lustig (00:37:13):

That you really didn’t have any control over, right? It was laid down before you were cognizant of what you were consuming. It was probably determined by what your mother ate more than what you ate.

Mike Haney (00:37:28):

Okay? So subcutaneous fat got us to metabolically healthy obesity, which is one of the terms I wanted to cover. The other one is thin outside fat inside, and I suspect that’s going to take us to visceral fat, correct?

Rob Lustig (00:37:41):

Exactly. So let’s take those Asians, those South Asians, they don’t have the fat cell number to be able to accommodate what’s coming in. So their perilipin border is going to stretch inordinately at a much lower body mass index. They’re going to start getting sicker earlier, but that’s in the subcu space. The fact is their subcu space can’t handle anymore. They’re going to start laying down fat in the metabolically active space. That’s the visceral fat, the fat around the organs. Now, the fat around the organs will do the same thing that the subcutaneous fat did. That is it will layer on, layer on. So the fat vacuole will get larger and larger. The perilipin border will also break down, and when it does, the grease will spill. It will choke off the cell, the cell dies. It will recruit macrophages to the cleanup crew janitors to get rid of the junk.

(00:38:50):

And that will then release cytokines in order to recruit more just like it did in the subcutaneous space. But now the difference is you’re in the visceral fat and the visceral fat does not drain into the systemic circulation. The visceral fat drains into the portal vein, the portal circulation. Now we have two kinds of circulations in our bodies. We have the systemic circulation and we have the two portal circulations. Now, what are the difference between them? The systemic circulation goes like this, heart, aorta, artery, arteriole, organ, venule, vein, vena cava, heart. Portal circulation goes like this, heart, aorta, artery, arteriole one, organ one, venule one, vein one, arteriole two, organ two, vein two, inferior vena cava, heart. In other words, the systemic circulation, every blood cell goes through one organ on the way back to the heart.

(00:40:23):

With a portal circulation, every blood cell goes through two organs on the way back to the heart. That’s what a portal circulation means is you’re going through two organs instead of one. Okay? Now that may seem kind of like dumb or stupid, but there’s information being carried in that portal circulation from one organ to the next that you don’t want to be messed up by diluting it in the general circulation. There are two portal circulations in the body. One is here, the hypothalamus to pituitary. And that’s because the hypothalamic releasing factors are in such short supply that if they went into the systemic circulation, your pituitary would never see it. So it has to go straight from the hypothalamus to the pituitary.

(00:41:09):

And the second portal circulation is pancreas liver. So that insulin signal from the pancreas is directed at the liver. That’s the primary target of insulin action is the liver. And so you want the pancreas when it releases insulin, you want it to go straight to the liver.

(00:41:34):

So it goes via the portal circulation. Now, what’s the volume of distribution in the portal circulation about 250 cc’s? What was the volume of distribution in the systemic circulation? 6,000 cc’s, 1/24th is large. So when you start getting cell death in the visceral adipose tissue, you’re going to raise that cytokine concentration that the liver sees much faster. And so that visceral fat will cause more metabolic perturbation and more damage from those cytokines reaching the liver because it was visceral adipose tissue versus subcutaneous adipose tissue. Even though the adipocytes themselves are not all that different, the visceral adipose tissue makes more metabolic mayhem.

(00:42:33):

And then finally, so how many kilos or pounds of visceral fat do you have to accumulate before your body starts getting sick? Remember, for subcutaneous fat, it was like 22 to 25. For visceral fat, it’s more like 4, 3 to 5, so, not that many.

(00:42:57):

So can you measure a 3 to 5 pound weight gain on the scale? The answer’s not really. I mean, it’s within the range of error. A good poop will throw you off by at least that much. And if you drink a beer, all bets are off. So 3 to 5 pounds is kind of within the range of error one way or the other. So you really can’t tell when your visceral fat’s getting big, except your belly is getting big. Your waist circumference is getting big because that’s where the visceral fat is here in your belly. And that’s why we always say that the belly fat or your waist circumference is more important than your weight. That’s right. Because your waist circumference is a manifestation of that visceral fat. And your weight is more of a manifestation of your subcutaneous fat. And that’s one of the reasons why BMI, which is really a measure of your subcutaneous fat is good for populations, but not for individual people.

(00:44:04):

And I’ve been railing against this with the American Diabetes Association forever, that we shouldn’t even categorize people as obesity based on BMI. Yeah, it’s okay when you want to do epidemiologic studies, ’cause that’s what you have, because that’s what people can get is height and weight. But the fact is, what you really want to know is what’s going on in the ectopic, visceral adipose tissue compartment or the liver fat compartment, which is even worse than the visceral adipose tissue. And the reason is because the liver fat is right there. It’s at ground zero causing the problems. I mean, if you wanted to disrupt New York City, would you set off bombs at individual local subway stations or would you basically blow up Grand Central Station? The liver’s Grand Central station. That’s where the action is. And so when the liver, which normally does not store fat, starts storing fat, now you got a big problem.

(00:45:20):

And the liver’s not specialized. It doesn’t have a fat vacuole, it doesn’t have a place with a border that keeps the fat away from the rest of the cell. The droplets just now form in the cell, and that disrupts things at a much lower level. So how many pounds or kilos of fat can your liver store before it gets sick? Half a pound, half a pound of fat before your liver starts manifesting metabolic dysfunction. So 22 to 25 pounds of subcutaneous fat equals 3 to 5 pounds of visceral fat equals a half a pound of liver fat in terms of metabolic mayhem. And can you measure half a pound on the scale? No way in hell. So there are people who have liver fat who are perfectly normal weight, who think they’re fine and they’re not. And this is what we call thin on the outside fat on the inside, TOFI.

(00:46:32):

So it’s the ectopic fat, the visceral fat, the liver fat that ultimately determines the degree of metabolic dysfunction, not the subcutaneous fat. That’s why you can have metabolically healthy obese people, and you can have metabolically unhealthy, thin people. It depends on where the fat is. And what determined that? Well, your fat cell number, which was determined by the age of two. So screw that. That’s not in your control. That’s not in your purview. And the insulin, because the more that goes to fat cells, the more likely you’re going to generate cytokines and the more chance for metabolic mayhem. So that’s the way you have to put this together.

Mike Haney (00:47:30):

So what impacts, you just touched on at the end there with the insulin, but we’ve been talking about this sort of in sequence, right? Subcutaneous fat, then your visceral fat, then your liver fat, which could leave the impression that you fill up that subcutaneous bucket first. When that starts overflowing, it goes to ectopic. When that overflows, it goes to liver. But if that were the actual case, then I couldn’t be thin on the outside with no real subcutaneous fat. And I don’t have that 20 pounds of that, but still have it in my liver. So what is determining where that fat distributes?

Rob Lustig (00:48:03):

So-

PART 2 OF 4 ENDS [00:48:04]

Mike Haney (00:48:03):

What is determining where that fat distributes?

Rob Lustig (00:48:03):

First of all, you are absolutely correct. It’s not as simple as, okay, you fill up one bucket, you start the second bucket, and you fill up the second bucket, you start the third bucket. No, no, no. It doesn’t work that way. Different things will cause the fat location to change. What drives the subcutaneous fat? The answer is, well, whatever you ate that had calories that got turned into lipid. The insulin’s going to drive it into that subcutaneous fat.

(00:48:34):

Calories can make subcutaneous fat. I don’t argue that. I don’t know. I’ve never argued that. You eat more calories than you burn, you will generate subcutaneous fat. I don’t argue that. People say I don’t believe in the first law of thermodynamics. Yes, I do. I absolutely do. I just don’t think that subcutaneous fat is the driver of disease. That’s the difference. Okay, next.

(00:49:02):

What generates visceral fat? Stress. Stress generates visceral fat. No stress, very little visceral fat. High stress, boatloads of visceral fat, irrespective of body weight. Cortisol drives visceral fat accumulation. Cortisol. We know this from the Whitehall II studies. We know this from a bunch of different studies. The degree of stress determines the degree of visceral fat. Cortisol drives visceral fat accumulation.

(00:49:42):

The most obvious and easiest disease to make this apparent is Cushing syndrome. What is Cushing syndrome is hypercortisolism usually due to an adrenal tumor or due to an ACTH secreting tumor that leads to the adrenal to make excess cortisol. You end up with muscle wasting, but you end up with huge belly, all visceral fat. Those patients have the worst metabolic dysfunction of anybody. It’s not because they’re gaining extra weight, it’s because it’s all getting turned into fat and being deposited in the belly.

(00:50:27):

What is so dysfunctional about stress? Two things. One, the cortisol, which we just mentioned. Cortisol is a driver of adipose tissue deposition. The reason is because if you’re stressed, your body is saying, “I better put some energy in a place I can access it quickly because I might need it to run away from the lion or evolutionarily.”

(00:50:57):

The point is, we didn’t have chronic stress due to hurricanes. We didn’t have chronic stress due to avoiding the lion on the savanna. We have chronic stress due to our sedentary lifestyle with bosses. Your boss is the driver of your visceral fat. That’s the only way to state it.

Mike Haney (00:51:22):

That’s the takeaway from this.

Rob Lustig (00:51:23):

No boss, no visceral fat. All right? Get rid of your boss. All right? Just don’t do it in a violent way. All right? But your boss is your problem, because that’s causing your chronic stress, and your chronic stress is driving that visceral fat.

(00:51:40):

There’s a second reason that stress does that. The adrenergic nervous system. Now everybody’s heard of the sympathetic nervous system by now. That’s the fight or flight reflex. That works acutely. How long can you manifest that adrenergic burst when you get frightened and you have to run away from the lion? How many minutes of energy, of excess glucose, of blood pressure can you manifest from the epinephrine release from the sympathetic nervous system in response to an acute stressful stimulus? About 10 minutes. Then that starts going down.

(00:52:29):

But you know what? If you run away from the lion and you’re starting to lose energy, you’re screwed, you’re lunch. That’s where cortisol picks up, at the ten-minute mark. It takes about 10 minutes for the adrenal gland to make cortisol to be able to be released because no storage place for cortisol. So you have to make it all from scratch, and it takes about 10 minutes to generate a cortisol response in response to a stressful stimulus.

(00:52:59):

Now you’ve got the cortisol being pretty much the only driver of that stress response, because you’ve done with the adrenergic. The adrenergic is still firing, it just doesn’t have the epinephrine because all of the vesicles are depleted.

(00:53:19):

Here’s what people don’t know that’s really important. You get the adrenergic response initially acutely. You get lipolysis. You get turning fat into energy at the level of the adipose tissue. Well, you then lose those vesicles. You’ve basically secreted them all, and you can’t make them fast enough. But the adrenergic nervous system is secreting a second hormone, not just the epinephrine. It’s secreting something called Neuropeptide Y. They co-localize. Norepinephrine and Neuropeptide Y co-localize.

(00:54:03):

Turns out Neuropeptide Y actually stops the adipose tissue from giving up fat. So you go from lipolysis to lipogenesis. The more chronic the stress, the more the lipogenesis. So between the excess cortisol and the Neuropeptide Y, you’re going to turn that fat cell, which was a storage form of ready energy, you’re going to turn it into basically a depot for extra energy storage. So you’re going to get increased visceral fat on the basis of the stress with the Neuropeptide Y and the cortisol.

Mike Haney (00:54:45):

Let me just make sure I’m following that. If your state of stress, what your body interprets as a state of stress such that it’s firing your fight or flight system, extends beyond 10 minutes, what’s the response then in your body is changing essentially from fat burning, going we need lots of energy to get away from the lion, to fat storage because the chemicals, the hormones that are driving that fat burning are depleted, the epinephrine, and the other chemicals are taking over saying, “Well, we think we’re going to need more energy continued here, so just let’s start packing it into the visceral fat where it’s going to be more readily available.”

Rob Lustig (00:55:20):

Correct, exactly right. It’s a physiologic response to the degree of stress, but it’s maladaptive in our environment. It was adaptive when all we had to worry about were lions and hurricanes. But now, because of bosses, it’s maladaptive. That’s the big problem there.

(00:55:42):

Then finally, liver fat. What makes liver fat? The answer is two things, sugar and alcohol. Alcohol, famous. Alcoholic fatty liver disease causes cirrhosis. Known about that only for about 500 years or so. That’s why we stuffed gooses with carbohydrate and especially sugar to make foie gras. Well, now we’re all foie gras for just that reason, because of sugar and alcohol. Sugar and alcohol are metabolized virtually identically.

(00:56:22):

The liver is where that metabolism occurs. The liver can’t process all of it. It inhibits the mitochondrial function, especially alcohol. So you end up turning all that excess energy into fat, and then the fat doesn’t get out. Now it precipitates in the liver. Now you’ve got fatty liver. Now you’ve got super insulin resistance. So the pancreas is going to make more insulin to make the liver do its job. That’s going to raise insulin levels all over the body. That’s going to drive even more weight gain elsewhere.

(00:56:55):

So you can have a sick liver and be thin, or you can have a sick liver and be fat. You can have a high stress job and be thin, or have a high stress job and be fat. But all in all, it’s about those ectopic depots that determine whether or not you have metabolic dysfunction.

Mike Haney (00:57:21):

What can we do about determining … We’ve talked about stress. We talked about caloric balance, which can drive some of this, and then sugar and alcohol. That would paint a picture that we can control, I don’t want to say completely control, but control to some degree our level of healthy versus non-healthy obesity or fat storage based on what we eat and how stressed we are.

Rob Lustig (00:57:48):

Correct.

Mike Haney (00:57:48):

What else plays into that, and where does something like exercise or fat burning play into that? If I’m thin on the outside, fat on the inside, but I go for a run, am I burning off my liver fat then, because that’s where my fat is stored?

Rob Lustig (00:58:01):

Indeed. You will access that metabolically active fat first. You will get that visceral fat to give up its lipid first. That’s one of the reasons why doctors will tell you, “Well, if you just lost 3% of your body weight, you’d get healthy.” That’s right. The reason’s because that 3% would be your visceral fat. It’s not going to be subcutaneous fat, promise. It ain’t going to change how you look in a bathing suit, but it is going to make you metabolically healthier.

(00:58:38):

The reason’s because your visceral fat will get burned off by that exercise first, that adrenergic response that we talked about. So you will get lipolysis of that visceral fat. It will go to the liver, turn into ketones [inaudible 00:58:52] be used for the rest of the body.

(00:58:55):

The only problem is that visceral fat will accumulate almost as quickly as it dissipated. So unless you keep the exercise up, it will turn right back around. You will reaccumulate it as fast as you lost it, sometimes even faster. That’s the biggest problem is if you’re going to use exercise as the modality of trying to deal with your metabolic dysfunction, you have to be consistent about it.

(00:59:25):

We know from multiple studies, especially the studies of George Brooks at UC Berkeley who’s a mitochondria expert, wonderful guy, absolutely … We should definitely do an interview with him. We know that once you stop exercising, you are back at baseline in two weeks. The effect of exercise is not durable. It does not last. You have to keep it up. Of course, that’s a problem for everybody.

Mike Haney (00:59:56):

So beyond exercise then … Exercise certainly plays a role. It’s playing a role not just because of the simple calories in calories out model, but because it is actually burning off that fat that you want to burn off. It’s using that.

Rob Lustig (01:00:11):

Exactly. You can’t burn off a Big Mac in terms of exercise. People are always talking, “Well, I’ll just exercise more.” Garbage. Not possible. You would have to exercise three hours to burn off one Big Mac. You would have to be basically a gridiron football player to burn off one Big Mac. Ain’t going to happen.

(01:00:39):

The reason why exercise is good is not because it burns calories. The reason is because it burns visceral fat. Visceral fat is good to lose, especially when your stress is continuing to accumulate it.

Mike Haney (01:00:58):

So diet, what you eat, is going to play a role. How much you eat and what you eat is going to play a role in just that baseline question of how much extra adipose tissue am I packing on.

Rob Lustig (01:01:10):

That’s correct.

Mike Haney (01:01:12):

Exercise and stress are going to play a role in where that stress, where that fat accumulates, exercise in where that fat gets burned off. So you essentially need that triad to work together. You need to be eating in such a way that you’re not directing that fat to the liver. So less sugar, less alcohol. You need to eat in such a way that you’re not driving the insulin up, because that’s going to drive more fat storage. Then you need to exercise to help burn off that visceral fat.

Rob Lustig (01:01:39):

The key to being healthy. That’s it.

Mike Haney (01:01:41):

Good. We’ve solved it.

Rob Lustig (01:01:42):

Diet and exercise. But not eat less, exercise more. It’s very specific, and it has very specific targets within the body in order to make it work.

Mike Haney (01:01:54):

Let’s touch on a couple other things quick. Obesity in children. You’re a pediatric endocrinologist. You’ve spent your career looking at obesity in children.

Rob Lustig (01:02:03):

Oh boy. Yeah.

Mike Haney (01:02:04):

This could obviously be a whole show on its own, but I’m just curious where … Maybe let’s frame it in this context of healthy versus unhealthy weight and obesity, and where we’re at as a society, these drivers we’ve just been talking about. Where are we at with childhood obesity, childhood overweight? Where are we at in the sense of do we know what’s driving it and do we know what to do about it?

Rob Lustig (01:02:28):

Oh boy.

Mike Haney (01:02:30):

You have 30 seconds.

Rob Lustig (01:02:34):

This is complicated. I actually give a talk called Growing Up With Obesity. The fact of the matter is we have obese newborns. We have an epidemic of obese newborns. They don’t diet and exercise. Four studies across the world, Russia Israel, South Africa, United States, the secular trend of birth weight over those four countries, and they’re all very different, is an increase in birth weight of 200 grams in that 25 year period. So babies are born half a pound heavier today than they were 25 years ago.

(01:03:14):

When you put those babies in a scanner, in a DEXA scanner, it turns out those 200 grams are all fat. We have obese newborns, but they didn’t eat anything yet. Exactly right. So why is the placenta laying down all of this excess fat in newborns. By the way, that’s going to drive fat cell number and make that a problem for that infant the rest of their life.

(01:03:46):

That’s what we are seeing. We are seeing the manifestation of that increased fat cell number due to the laying down of prenatal, neonatal fat due to whatever the mother was exposed to. That ain’t the kid’s fault.

(01:04:08):

This whole concept of childhood obesity being about ultra-processed food, yes. Yes because that’s causing the growth of those fat cells. But we already have a problem with the number of those fat cells. What happened there? What made that?

(01:04:24):

Well, part of it is what the mother ate. We used to think that fructose, a sweet molecule in sugar which causes mitochondrial dysfunction, it inhibits three enzymes in the mitochondria that generate lipogenesis; AMP kinase [inaudible 01:04:41] acyl-CoA dehydrogenase long chain; and CPT-I, carnitine palmitoyltransferase I; all of these are necessary to get those mitochondria to burn energy and generate ATP at the rate that they should. Fructose inhibits all three of those. So mitochondria not working as well, and if they’re not working as well, you’re going to end up with the substrate going to fat. So that’s driving that fat.

(01:05:09):

We used to think that mother’s fructose consumption never reached the fetus. The reason we thought that was kind of dumb. The reason we thought that was because the transporter for fructose, called Glut-V, is not in the placenta. So [inaudible 01:05:27] It’s not there. That’s true. Placenta does not have Glut-V. It has Glut-VII, IX and XI, and they transport fructose as well. They’re just not specific for fructose like Glut-V is. They transport both glucose and fructose. So we weren’t looking for the right thing.

(01:05:48):

The amount of sugar that the mother consumes during pregnancy is affecting that fetus adversely, and driving that fat and the fat cell number, and putting that kid at risk for the rest of his life or her life. That’s one.

(01:06:12):

In addition, we have a whole host of chemicals that are in our environment. We call them environmental obesogens. An obesogen is a chemical that induces adiposity separate from its caloric content.

(01:06:34):

Most of these environmental obesogens don’t have calories, like BPA doesn’t have calories. Phthalates don’t have calories. Parabens don’t have calories. PFAS doesn’t have calories. But they are strewn throughout our entire environment and they inhibit mitochondria. They inhibit mitochondria in the same way fructose does. So you’re going to end up taking the substrate and turning it into fat exclusive of what the mother ate. Babies are basically bathed in this. Turns out PFAS is in breast milk.

(01:07:18):

Number three, microplastics. This is new. Paper just came out two weeks ago showing that the microplastic burden predicts fatty liver. Well, I hate to tell you, but your brain right now, sitting here as we speak, is now one 200th plastic.

Mike Haney (01:07:44):

That explains a lot.

Rob Lustig (01:07:45):

0.5% of your and my brain is now plastic. It’s got to be doing something. Is it the cause of Alzheimer’s? Is it the cause of mental health disorders? We don’t know yet. Could be. Point is that has nothing to do with calories except that a lot of the calories were in the plastic before they got consumed. The biggest plastic polluters are Coke and Pepsi. Is that a surprise?

(01:08:17):

Point is these environmental obesogens, what they do is they are molecular mimics. They basically tell the fat cell to either divide or grow or inhibit burning in such a way as to generate excess fat tissue irrespective of calories.

(01:08:39):

We can’t get rid of them. They’re forever chemicals. I just heard a report this morning that said that if we initiated a superfund cleanup of all the toxic chemicals in the world, it would be greater than the GDP of the entire world. We can’t do it. Can’t be done. Even if we had the wherewithal to do it, we couldn’t do it. We’re stuck with these.

(01:09:09):

Now the question is how much of a role do these environmental chemicals play. Back-of-hand envelope calculation, I would say probably about 20%. That means 80% of it’s the food. Oh, by the way, and the air pollution. The air pollution, particulate matter 2.5 millimeters or smaller is pro- inflammatory. Pro-inflammatory means insulin resistance also. So that’s going to generate high insulin levels. That’s going to generate weight gain.

(01:09:39):

A lot of these things had nothing to do with food, right? The microplastics didn’t have anything to do with food. The BPA, et cetera. The air pollution didn’t have anything to do with food or exercise. If you’ve got newborns with obesity, how can it be about food? Well, it could be about mother’s food, but then how are you going to fix that? Well, you have to fix the whole food supply.

(01:10:06):

So this is extraordinarily complex. People want to make it easy because it hurts your brain to think about all the different components that go into it. Yeah, it hurts my brain too. But the fact of the matter is this is a very difficult systems biology problem having to do with mitochondrial dysfunction and ATP generation, and anything that inhibits that …

(01:10:36):

I forgot one more thing. Ionizing radiation. Ionizing radiation causes mitochondrial dysfunction too. We know that from the International Space Station, because if you look at the metabolome of the urine of the astronauts, it shows very clearly that mitochondrial metabolites are basically going in the wrong direction because you’re up in space and you basically have more ionizing radiation. Well, we have more ionizing radiation on the ground too.

(01:11:06):

So how are we going to fix that? Well, let’s fix what we can fix. That’s the way I look at it. If 80% of it is the food, and if fructose is the most egregious denizen of the deep here in terms of causing the problems, and it’s the one that the food industry specifically added to the food for its purposes, not for yours, why don’t we start with that? Because that we could do something about.

(01:11:39):

We’re not going to be able to get the BPA out of the environment. We’re not going to be able to get the PFAS out of the environment. We’re not going to be able to pull up all the vinyl flooring in the world. We’re not going to be able to do a lot of the things that are necessary to rid ourselves of these environmental chemicals. But the one environmental chemical that we could do something about today is fructose.

Mike Haney (01:12:01):

I think this question will tie a lot of this together.

PART 3 OF 4 ENDS [01:12:04]

Mike Haney (01:12:03):

… is fructose. I think this question will tie a lot of this together when we talk about people who are medically healthy obese, and those might be folks who look in the mirror and feel that they’re obese. And we’ve got folks who are thin on the outside, fat on the inside, they think they’re healthy, they don’t realize that they’re actually unhealthy until it starts to manifest. Then we’ve got kids who might be born obese or who, through all these things we just talked about, are getting obese.

(01:12:26):

The way to treat this nowadays is a GLP-1. So talk about the role… And I’ll mention we have a whole podcast on obesogens with you and Casey and we also have a whole podcast on GLP-1 so we can do the deep dive on that, but maybe just as a way to wrap this up and to kind of bring it to the current quote unquote “solution,” what is the role that GLP-1 is playing in this physiological story we’ve been telling, and who is it appropriate for, and when, out of these groups we just talked about?

Rob Lustig (01:12:53):

I wish I knew the answer to either of those. I’ll do my best to try to cobble together what we do know. It’s a complex problem. I think that food intake is a problem, but I don’t think it’s the biggest problem. I think mitochondrial function is the biggest problem. And the reason I say that is because the diseases that we are suffering from, the diseases that are overburdening the medical healthcare system, type II diabetes, hypertension, dyslipidemia, cardiovascular disease, cancer, dementia, fatty liver disease, polycystic ovarian disease, these eight diseases are all the diseases of mitochondria and they’re occurring in normal weight people too, not just obese people. If it was about food intake, quantity food intake, then that would not be the case, but these are all mitochondrial dysfunctions that are occurring in normal weight people. So I think the mitochondria are where the action is.

(01:14:01):

Do GLP-I analogs affect the mitochondria? And the answer is no, not directly anyway. They affect the mitochondria in an indirect way because they reduce food intake. They do reduce food intake, and we’ll talk about why in a minute. And reducing food intake means that there’s less substrate having to be processed through the mitochondria, so less substrate, less problem. So in that respect, we can see an improvement. And in fact, Novo Nordisk and Eli Lilly have data to show that using GLP-I analogs can help type II diabetes, can help heart disease. We’re still looking at the cancer, dementia, fatty liver disease. I actually saw a paper on GLP-I’s helping fatty liver disease. I think it’s because there’s less substrate. Now that’s not bad, but it’s not affecting the mitochondria directly.

(01:15:05):

I think if we affected the mitochondria directly, we’d have even something better to be able to hang our hat on. Now, GLP-I analogs can help. I’m not against them. I’m actually for them clinically because they do work and we have a lot of people with morbid obesity who either need bariatric surgery or a, GLP-1 analog. And if we can treat them with a GLP-I analog and do as well as bariatric surgery, ultimately, that’s a good thing. So I’m not against them. People think I’m against them. I’m not against them.

(01:15:47):

But the question is why do they work? Well, they work because of delayed gastric emptying. They basically make your intestine move the food through the intestine slower. Well, if you’re moving the food through the intestine slower, that means you’ve got a backup. If you’ve got a backup, that means your stomach hasn’t emptied before you’re ready to eat again, you get nauseated, okay? You might vomit.

(01:16:17):

Now, those two things seem to get better with time, but there are two things that don’t get better with time. Pancreatitis, and if you get pancreatitis, you’re in deep doo-doo. That is a bad thing. And worse yet, gastroparesis, stomach turns to stone because it’s not moving, stomach is paralyzed. It turns out that’s 3.4% of people who go on a GLP-I analog get gastroparesis.

(01:16:46):

By the way, Novo Nordisk and Eli Lilly don’t want you to know that, so it’s not on the package insert. But there are lawsuits against both companies for people who’ve developed gastroparesis because of these GLP-I analogs. Is this the right way to be treating this? I don’t know. I mean, if you’re sick, if you’re sick from your metabolically unhealthy obesity, maybe so if there’s nothing else that will save your life. If it’s six feet under or GLP-I analog, if that’s your choice, then go with the GLP-I analog. I’m for it. But for everyone else, I think this is a big problem because it’s not addressing the real problem. It’s not addressing what’s going on inside your cell. It’s a fix. It’s a band-aid because the real problem is inside the cell. Fix that, and then maybe we wouldn’t need GLP-I analogs.

Mike Haney (01:17:58):

Right. So if I’m somebody who is 15 pounds overweight and it’s largely subcutaneous, taking a GLP-I is probably going to help me lose that because it’s simply going to reduce my caloric intake.

Rob Lustig (01:18:11):

At some point, yeah.

Mike Haney (01:18:12):

Which is not necessarily beyond the mechanical. It’s not affecting the metabolic health state.

Rob Lustig (01:18:19):

It’s affecting it in that you have less substrate that has to be processed by a limited number of defective mitochondria, but it’s not making those mitochondria better.

Mike Haney (01:18:30):

And if I’m thin on the outside, but I’ve got ectopic or liver fat, is the GLP-I helping me in any way?

Rob Lustig (01:18:38):

It’s going to reduce substrate. That might help. But if you’re stressed, you’re still going to be stressed. If you’ve got visceral fat, you’re still going to have visceral fat and you’re still going to have problems.

Mike Haney (01:18:47):

Right. So I guess it brings it back to it’s essentially a band-aid.

Rob Lustig (01:18:52):

It’s a band-aid.

Mike Haney (01:18:53):

Right.

Rob Lustig (01:18:54):

It’s a band-aid. It’s not solving the problem. You got to solve the problem.

Mike Haney (01:18:59):

Right.

Rob Lustig (01:18:59):

You have to work upstream of the problem to solve the problem. GLP-I analogs are working downstream of the problem. They’re dealing with the result of the problem. In addition, it’s not the subcutaneous fat that’s metabolically dangerous. It’s the visceral and the liver fat, and the GLP-I analogs don’t specifically work on those.

Mike Haney (01:19:19):

Right. So the last question then, how do I know if I’ve got that visceral and particularly that liver fat? You mentioned that the quantities are so little, it’s not going to show up on my scale. How do I know that that’s my problem?

Rob Lustig (01:19:33):

Well, so there’s the free way, the cheap way, and the super expensive way, and you can choose. The free way is measuring your waist circumference, because if your waist circumference is high, then there’s a good chance that that’s because of visceral fat. And also when you have visceral fat, the chances are you have liver fat, too. That’s the easy one. The problem with that is, number one, the inter observer variability. And number two, the standards because different races, different ethnicities, different sexes, different ages are going to give you different reference ranges for waist circumference.

(01:20:17):

In general, for adults, we say 40 inches for men, 35 inches for women. Those are kind of the upper limit of normal for waist circumference, but it’s free and your doctor should do it except they don’t. Why don’t they do it? Well, doing it, number one, means doing it consistently and looking at the results over time. And number two, a lot of doctors don’t want to get that personal with patients for one reason or another. They used to, but they don’t anymore. So that’s the free way.

(01:20:54):

The cheap way is your blood tests. So what blood tests can tell you about visceral fat? The answer is your ALT will tell you about liver fat, alanine aminotransferase, but you have to interpret it correctly. And we did a whole podcast on what lab tests to draw, and the problem with ALT is the reference range. And so your doctor needs to know how to interpret it properly. For him to say it’s normal is useless. Never accept normal from your doctor. If there’s one piece of admonishment I want to give the audience, it is Hold your doctor’s feet to the fire, get the numbers, even if you don’t know how to interpret it, I do. Help me help you. Give me numbers and I’ll help you.

(01:21:52):

And then there’s the super expensive ways, which are basically scanning maneuvers. So you can do magnetic resonance spectroscopy, that’s what we did in our kids study, which will actually tell you exactly how much visceral and liver fat there is. Elastography, there’s a bunch of different imaging techniques, but they’re very expensive and often just for research. So go with what you have.

Mike Haney (01:22:24):

Where does the DEXA scan fit into that?

Rob Lustig (01:22:26):

Well, the DEXA scan is good, but it doesn’t tell you what’s visceral versus what’s total body. You can make some guesses, some guesstimate, about trunk to total body and do some ratios that can kind of give you some info on that, but it’s not a direct measurement. So it’s there, it’s not expensive, so that’s good, but it’s not going to be perfect. Oh, a liver ultrasound will also, that’s not too expensive. The problem with liver ultrasound is the lower range. It won’t see liver fat below 5%, so you kind of need to know what you’re looking for to figure out what the best modality is.

Mike Haney (01:23:15):

Yeah, I mean, I think this unpacking more of… You almost want to pull up pictures of 10 different people at different sizes and go, “What do we know about what’s going on here?” But it feels like… That’s interesting to me from an explanatory standpoint, from understanding a physiology of it, but the reason I go there is I feel like the takeaway from this is worry about your metabolically unhealthy obesity.

Rob Lustig (01:23:40):

That’s exactly the point I’m trying to make. Worry about your topic fat. Worry about your visceral and liver fat, that’s ectopic fat. If you do that, you are 95% of the way there.

Mike Haney (01:23:54):

Right.

Rob Lustig (01:23:54):

Absolutely. I couldn’t agree more. I hope I tried to make that clear. That’s the issue. And so your stress, your sugar and your alcohol, that’s what you have to worry about. So how do you deal with your stress? Well, however you deal with it. If it’s exercise, okay, if it’s mindfulness, okay, if it’s sleep, improving sleep, okay. Whatever it is that improves your stress is good for that visceral fat. For the liver fat, anything that gets your sugar and alcohol consumption down is good. You do those two things, and you are 95% of the way there, but people can’t or don’t or won’t or whatever.

Mike Haney (01:24:48):

I mean, the reason I think it’s important to highlight that and let that be a takeaway is I think people are confused about what to do. I think people hear a lot-

Rob Lustig (01:24:56):

Oh, yeah, yeah.

Mike Haney (01:24:57):

… of different advice and they don’t understand their own physiology understandably, we’re not taught any of this. I wasn’t, anyway.

Rob Lustig (01:25:04):

No, no. This stuff is about 15 years old now and it takes 25 years before anything gets into the medical textbooks, so they don’t know. And that’s one of the reasons why I do these podcasts and why I’m happy to be associated with Levels is because it gives a forum for getting this information out. Do you know how many doctors come email me and thank me because they didn’t know this stuff, they didn’t learn this stuff in medical school and how it’s helped both them and their practices? Okay, it happens. I probably get three a day, at least three a day.

Mike Haney (01:25:38):

We talked about several things in here that we don’t really know yet, but this does feel like one of these areas in terms of the difference between where the fat tissue is or the fat cells are, the what is healthy versus unhealthy, that we’ve got a pretty good research basis for that. That feels like there’s a pretty high level of confidence at this point in those kinds of things we were just talking about. Would you agree with that?

Rob Lustig (01:26:00):

Yeah. I think so, yes. Anybody who’s still talking about fat as a single unitary concept is just wrong, is just not keeping up. And anybody who’s talking about calories as being a single unitary concept is just wrong. But we have all the data for that, but I’ll tell you, it’s like pulling teeth sometimes.

Mike Haney (01:26:27):

So one of the things we talked about in the beginning of this is the kind of, let’s call it social movements around obesity, and one of them sort of takes the name of healthy at any size, and what I’m taking from this conversation is healthy at any size is not inherently wrong, but it might be missing the point.

Rob Lustig (01:26:46):

What I would rather call it is subcutaneous fat at any size. I don’t care what your subcutaneous fat is, okay? So if you are obese and it’s because of subcutaneous fat, fine, no problem. You do you. It’s a non-issue. It’s non-issue medically, and it should be a non-issue culturally. Subcutaneous fat is personal and not the problem. Visceral and liver fat is the problem. Now, as it turns out, visceral and liver fat occurs in normal weight people as well as obese people.

(01:27:33):

The healthy at any size is missing the point about the three components. If you have visceral and liver fat, it is in your best interest, and ultimately society’s best interest from a medical care standpoint, to do something about it. So when I hear people say healthy at any size, I say, “What do you mean by that?” If the answer is subcutaneous fat at any size because they are exercising, because they are doing what they can to reduce stress, because they are actually curbing their sugar intake and their alcohol intake to be healthier, to make their mitochondria work better, then I am totally for it. I am on board with them, but frequently that’s not the case. So I have a lot of teaching and explaining to do.

Mike Haney (01:28:36):

Let’s maybe add one more potentially politically charged topic onto that because I think this fits in. I think so much of the challenge around the obesity debate or the obesity discussion within society comes down to this question of agency, right? The easy thing to do, particularly for thin folks, is to look at somebody who’s overweight and go, “Lazy, not exercising, no self-control, can’t do it.” And what the folks who are obese are often saying is, “No,” exactly as you just said, “I’m exercising. I’m doing all the things. Stop coming at me, bro, with this calling me lazy kind of side.”

Rob Lustig (01:29:11):

Exactly.

Mike Haney (01:29:11):

Where does agency, self-control fit into this story?

Rob Lustig (01:29:15):

All right, as far as I’m concerned, self-control is not the issue. Self-control is a matter of quote “personal responsibility.” I’ve actually just written a full chapter on the concept of personal responsibility. Personal responsibility is an ideology. It’s not a precept. It’s an ideology. It’s not in the constitution, it’s not in the Declaration of Independence, it’s not in the Magna Carta. There is no personal responsibility in any of those things. Yet, we levy personal responsibility as an excuse to blame. We say freedom of choice, but freedom to blame. It’s really the freedom to blame. And that’s what this concept of personal responsibility is turned into.

(01:30:07):

So self-control is basically just personal responsibility turned inward. There is no personal responsibility, and we know that because obesity is a biochemical problem, not a behavioral one. People think if you eat it, you better burn it or you’re going to store it. Wrong, wrong. It’s more, if you’re going to store it and you expect to burn it, then you’re going to have to eat it. In which case the two behaviors we associate with obesity, the gluttony and the sloth, are actually secondary to the biochemical process of the insulin going up. So it’s the insulin that’s driving the behaviors, and we’ve proven that. So things that make your insulin go up generate those behaviors irrespective. And unfortunately, a lot of the things that make insulin go up are things in the environment that have nothing to do with your behaviors.

(01:31:10):

So this whole concept of blaming the victim is just completely off base. Every personal responsibility health issue becomes a public health crisis and has throughout all of history, tuberculosis, HIV, pick your scourge. They all started out as personal responsibility issues. Ultimately, science proved that wrong. Science has already proved the obesity epidemic as being wrong on this personal responsibility issue. I’m not saying that people should not exercise whatever agency they can muster up, I’m for that. But the fact is that society cannot blame an individual for obesity in the same way they can’t blame a newborn for obesity.

Mike Haney (01:32:11):

So it’s not while we have agency to control some of the things we’ve been talking about, reducing your stress, paying attention to sugar and alcohol intake, exercising, if you are obese, it’s not because you failed to do those things?

Rob Lustig (01:32:28):

Correct. This has nothing to do with failure. You are not a bad person. You are a good person, and if you try to help yourself, you’re even a better person.

Mike Haney (01:32:44):

I think the thing you’re getting at with the insulin is the food environment.

Rob Lustig (01:32:47):

Fix the environment.

Mike Haney (01:32:48):

It’s very, very difficult to achieve a sort of perfect score on these things that we just talked about.

Rob Lustig (01:32:56):

Exactly.

Mike Haney (01:32:57):

On this reduced stress, on this no sugar and alcohol. It’s not impossible, but it’s harder now than it was a hundred years ago.

Rob Lustig (01:33:04):

Exactly right. Anthony Cashmore, head of biology at the University of Pennsylvania, member of the National Academy, published a paper many years ago, 2008, in PNAS, called the Lucretian Swerve Personal Responsibility and the Justice System, basically argued that personal responsibility was something we invented in order to punish perpetrators. I feel the same way.

(01:33:32):

Ultimately 50% of obesity is genetic. I don’t argue that. 50% is environmental with some random stochastic processes thrown on top of it. Well, the genetic part is genetic, but that didn’t change in the last 50 years. The random stochastic processes are random and you can’t control those. So what’s left? The environment, that’s something we could do something about, like get the sugar out of the food because we know that that’s interfering with mitochondrial function. Let’s do what we can as a society to solve the problem for everyone instead of blaming people for things they can’t solve.

PART 4 OF 4 ENDS [01:34:31]